With the understanding of microRNA (miRNA or miR) functions in tumor initiation, progression, and metastasis, efforts are underway to develop new miRNA-based therapies. Very recently, we demonstrated effectiveness of a novel humanized bioengineered miR-124-3p prodrug in controlling spontaneous lung metastasis in mouse models. This study was to investigate the molecular and cellular mechanisms by which miR-124-3p controls tumor metastasis. Proteomics study identified a set of proteins selectively and significantly downregulated by bioengineered miR-124-3p in A549 cells, which were assembled into multiple cellular components critical for metastatic potential. Among them, plectin (PLEC) was verified as a new direct target for miR-124-3p that links cytoskeleton components and junctions. In miR-124-3p-treated lung cancer and osteosarcoma cells, protein levels of vimentin, talin 1 (TLN1), integrin beta-1 (ITGB1), IQ motif containing GTPase activating protein 1 (IQGAP1), cadherin 2 or N-cadherin (CDH2), and junctional adhesion molecule A (F11R or JAMA or JAM1) decreased, causing remodeling of cytoskeletons and disruption of cell–cell junctions. Furthermore, miR-124-3p sharply suppressed the formation of focal adhesion plaques, leading to reduced cell adhesion capacity. Additionally, efficacy and safety of biologic miR-124-3p therapy was established in an aggressive experimental metastasis mouse model in vivo. These results connect miR-124-3p−PLEC signaling to other elements in the control of cytoskeleton, cell junctions, and adhesion essential for cancer cell invasion and extravasation towards metastasis, and support the promise of miR-124 therapy.

随着对 microRNA（miRNA 或 miR）在肿瘤发生、进展和转移中的功能的了解，人们正在努力开发新的基于 miRNA 的疗法。最近，我们证明了一种新型人源化生物工程 miR-124-3p 前药在控制小鼠模型自发性肺转移方面的有效性。本研究旨在探讨miR-124-3p控制肿瘤转移的分子和细胞机制。蛋白质组学研究确定了 A549 细胞中经过生物工程改造的 miR-124-3p 选择性且显着下调的一组蛋白质，这些蛋白质被组装成对转移潜力至关重要的多种细胞成分。其中，plectin（PLEC）被证实是连接细胞骨架成分和连接点的 miR-124-3p 的新直接靶标。在 miR-124-3p 处理的肺癌和骨肉瘤细胞中，波形蛋白、talin 1 (TLN1)、整合素 beta-1 (ITGB1)、含有 GTPase 激活蛋白 1 (IQGAP1) 的 IQ 基序、钙粘蛋白 2 或 N-钙粘蛋白的蛋白水平(CDH2) 和连接粘附分子 A (F11R 或 JAMA 或 JAM1) 减少，导致细胞骨架重塑和细胞-细胞连接破坏。此外，miR-124-3p 急剧抑制粘着斑的形成，导致细胞粘附能力降低。此外，生物 miR-124-3p 疗法的有效性和安全性是在侵袭性实验性转移小鼠体内模型中建立的。这些结果将 miR-124-3p−PLEC 信号传导与控制细胞骨架、细胞连接和粘附的其他元件联系起来，这些元件对于癌细胞侵袭和外渗转移至关重要，并支持 miR-124 治疗的前景。